Abstract

Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol lambda) is suggested to function in base excision repair (BER) and non-homologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single nucleotide polymorphism (SNP) encoding R438W Pol lambda was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol lambda in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen was assessed as it is commonly used in hormone replacement therapies and is a known breast cancer risk factor. Interestingly, the combination of estrogen treatment and the expression of the R438W Pol lambda drastically accelerated the rate of transformation. Estrogen exposure produces 8-oxoguanine lesions that persist in cells expressing R438W Pol lambda compared to WT Pol lambda-expressing cells. Unlike WT Pol lambda, which performs error-free bypass of 8-oxoguanine lesions, expression of R438W Pol lambda leads to an increase in mutagenesis and replicative stress in cells treated with estrogen. Together, these data suggest that individuals who carry the rs3730477 POLL germline variant have an increased risk of estrogen-associated breast cancer.
Implications: The Pol lambda R438W mutation can serve as a biomarker to predict cancer risk and implicates that treatment with estrogen in individuals with this mutation may further increase their risk of breast cancer.